Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States, and recent evidence indicate that the incidences of CRC has increased in adults <50 years of age. As such, new prevention strategies are urgently needed. ONC201 is a small molecule drug candidate with in vitro cytotoxicity associated with the induction of TNF-related apoptosis-inducing ligand (TRAIL), and subsequent TRAIL-dependent cell death. In vivo, ONC201 induces TRAIL and causes potent antitumor effects when administered as a single dose in mice with human CRC xenografts. A phase I clinical trial with ONC201 in patients with advanced solid tumors, showed some evidence of efficacy (stable disease) at doses that were well tolerated (no drug-related toxicities greater than grade 1). Micromolar plasma concentrations were achieved in these subjects after oral dosing, concentrations that were in the preclinical therapeutic range. ONC-201 is currently being tested in a phase II clinical trial in subjects with select advanced solid tumor cancers. The purpose of this Task Order is to determine whether ONC201 has chemopreventive activity in a mouse CRC model.